Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of β‐Lactamases

Егоров, А.М.; Mariya, Ulyashova; Rubtsova, M. Yu.

doi:10.1002/9781119282549.ch6

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“…The TEM-type βL family is characterized by a high degree of mutability (~30% of amino acid residues were found to mutate). Some of the mutations affect the substrate specificity, enzyme activity, and thermal stability [16,17]. At the same time, the Ω-loop is a highly conserved region (Figure 7).…”

Section: The Effect Of Mutations In ω-Loop Residues On Properties Of mentioning

confidence: 99%

“…The Ω-loop is located at the bottom of the entrance to the enzyme active site and includes the catalytically important and highly conserved residue Glu166, the mutation of which leads to an almost complete loss of enzyme activity. This review focuses on the structural peculiarities of the Ω-loop of TEM-type βLs-the most versatile group of serine class A enzymes that still remain one of the most common βLs among bacterial clinical pathogens and soil bacteria [16,17]. A detailed analysis of the loop is carried out in order to establish its role as a site of the allosteric regulation of activity and the specificity of βLs, as well as a potential target for novel inhibitors.…”

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The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

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Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme's active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM-type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl-enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.Biomolecules 2019, 9, 854 2 of 16 of inhibitors, whose structures are based on the β-lactam ring, is also limited because resistance to them has also developed. Today, a promising trend is to design novel βL inhibitors and simultaneously use them with antibiotics [7,8]. Computer methods involving the in silico search of novel inhibitors has significantly broadened the range of potential inhibitors. However, only a limited number of novel βL inhibitors have been found that are of non-β-lactam nature and are capable of binding close to the enzyme's active site [8][9][10][11]. Because of the relatively low inhibition constants of such inhibitors, this area of research needs to be further developed.Recently, special attention has been paid to studying the role of loops and peptide linkers as flexible elements in the functioning of proteins and enzymes [12,13]. The loops, as secondary structural elements of proteins, are characterized by an enhanced mobility; their role is not solely confined to being connecting units [12]. Furthermore, changes in the amino acid composition of the loops may impart new functions to protein superfamilies. The Ω-loops, a special class of loops with a conformation resembling the Greek letter "omega," are currently attracting specific attention. The loop conformation is ensured by the short-distance fixation of terminal amino acids. Ω-Loops have been observed in 60 proteins [13], some of which have been found to be involved in allosteric regulation during biospecific ligand recognition [14,15]. The structure of serine class A βLs represents a compact, conserved scaffold that consists of secondary structural elements linked by flexible loops. The Ω-loop is located at the bottom of the entrance to the enzyme active site and includes the catalytically important and highly conserved residue Glu166, the m...

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Section: The Effect Of Mutations In ω-Loop Residues On Properties Of mentioning

confidence: 99%

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confidence: 99%

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

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show abstract

Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of β‐Lactamases

Cited by 1 publication

References 47 publications

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

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